Though generally not perceived as an “extreme” environment, the global open ocean is a desert with respect to the organic and inorganic building blocks required to promote the growth of any potential inhabitants. In illuminated surface waters where light energy available for photosynthesis abounds, thermal stratification of the water column results in the constant starvation of (primarily microscopic) photoautotrophs for inorganic nutrients such as nitrogen and phosphorus. In the dark ocean interior, inorganic nutrients are generally in excess; however, organic carbon compounds are in short supply, and the stocks that are present are generally considered to be inaccessible as substrates to sustain active cell growth and metabolism. In spite of all of this, massive populations of microscopic cells abound in the global open ocean. Assessments based on gene- and genome-based measures have revealed a tremendous amount of diversity within the microbial plankton, but also that a vast majority of this diversity is not currently represented in existing culture collections of marine microorganisms. However, a combination of approaches that permit the interrogation of in situ microbial communities, such as environmental metagenomics, and methodological developments aimed at cultivating microorganisms present in numerically high abundance in the environment, such as high-throughput cultivation, are facilitating an unprecedented understanding of oligotrophic marine microorganisms and the roles they play in global ocean ecology.